Adenosine stress CMR perfusion imaging of the temporal evolution of perfusion defects in a porcine model of progressive obstructive coronary artery occlusion.

Adenosine stress CMR perfusion imaging can quantify absolute perfusion and myocardial perfusion reserve (MPR) in coronary artery disease (CAD) with higher spatial resolution than positron emission tomography, the only clinically available technique for quantitative myocardial perfusion imaging. While porcine models of CAD are excellent for studying perfusion abnormalities in chronic CAD, to date there are a limited number of studies that use quantitative perfusion for evaluation. Therefore, we developed an adenosine stress CMR protocol to evaluate the temporal evolution of perfusion defects in a porcine model of progressive obstructive CAD. 10 Yucatan minipigs underwent placement of an ameroid occluder around the left circumflex artery (LCX) to induce a progressive chronic coronary obstruction. Four animals underwent a hemodynamic dose range experiment to determine the adenosine dose inducing maximal hyperemia. Each animal had a CMR examination, including stress/rest spiral quantitative perfusion imaging at baseline and 1, 3, and 6 weeks. Late gadolinium enhancement images determined the presence of myocardial infarction, if any existed. Pixelwise quantitative perfusion maps were generated using Fermi deconvolution. The results were statistically analyzed with a repeated mixed measures model to block for physiological variation between the animals. Five animals developed myocardial infarction by 3 weeks, while three developed ischemia without an infarction. The perfusion defects were located in the inferolateral myocardium in the perfusion territory of the LCX. Stress perfusion values were higher in remote segments than both the infarcted and ischemic segments (p < 0.01). MPR values were significantly greater in the remote segments than infarcted and ischemic segments (p < 0.01). While the MPR decreased in all segments, the MPR recovered by the sixth week in the remote regions. We developed a model of progressive CAD and evaluated the temporal evolution of the development of quantitative perfusion defects. This model will serve as a platform for understanding the development of perfusion abnormalities in chronic occlusive CAD.

Pharmacological stress myocardial perfusion imaging with the potent and selective A(2A) adenosine receptor agonists ATL193 and ATL146e administered by either intravenous infusion or bolus injection.

BACKGROUND: Adenosine (Ado) and dipyridamole are alternatives to exercise stress for myocardial perfusion imaging. Though generally safe, side effects frequently occur that cause patient discomfort and sometimes lead to premature termination of the study or require aminophylline administration. Recently, a new class of A(2A) Ado receptor agonists was synthesized. ATL193 and ATL146e are 2-propynylcyclohexyl-5'-N-ethylcarboxamido derivatives of Ado. The study goals were to evaluate the potency and selectivity of these new compounds on recombinant canine Ado receptors and to evaluate their hemodynamic properties in dogs to assess their usefulness as vasodilators for myocardial perfusion imaging. METHODS AND RESULTS: In assays of recombinant canine Ado receptors, ATL-193 and ATL-146e were highly selective for the A(2A) over the A(1) and A(3) receptors and were more potent than MRE-0470 and CGS-21680. In 16 anesthetized dogs, the agonists were administered by infusion (ATL-193; n=7 normal) or bolus injection (ATL-146e; n=9 critical left anterior descending coronary artery stenosis), and hemodynamic responses were compared with those of Ado. Both agonists produced dose-dependent coronary flow (CF) elevation without provoking the hypotension observed with Ado. After an ATL-146e bolus, the CF increase was sustained for several minutes, providing ample time for injection and myocardial uptake of (99m)Tc-sestamibi, and CF returned to baseline within 20 minutes. The CF increase was completely blocked by the selective A(2A) antagonist ZM241385 (3 microgram. kg(-1). min(-1)). CONCLUSIONS: ATL-193 and ATL-146e are highly potent and selective Ado A(2A) receptor agonists with excellent potential for use as vasodilators for myocardial perfusion imaging. An important advantage of ATL-146e is the ability to administer it by bolus injection.

Assessment of residual coronary stenoses using 99mTc-N-NOET vasodilator stress imaging to evaluate coronary flow reserve early after coronary reperfusion in a canine model of subendocardial infarction.

UNLABELLED: Reperfusion is often incomplete after recanalization therapy because of the presence of residual coronary stenoses. Detecting mild to moderate stenoses requires assessing coronary flow reserve with vasodilator stress. 99mTc-(N-ethoxy-N-ethyl-dithiocarbamato)nitrido (N-NOET) is a viability-independent flow tracer and thus may be well suited for assessing coronary flow reserve in the acute phase of reperfusion. METHODS: Twelve open-chest dogs underwent 60 min of total left anterior descending artery (LAD) occlusion followed by either full reperfusion (group 1; n = 4) or reperfusion through a residual critical stenosis (group 2; n = 8). 99mTc-N-NOET was given during peak vasodilator stress 165 min after reperfusion, and initial and 60-min delayed images were acquired. Regional blood flow was assessed with radiolabeled microspheres. RESULTS: Infarct size was similar in both groups (9% +/- 2% vs. 8% +/- 2% of left ventricle). Both initial (0.61 +/- 0.02 vs. 0.73 +/- 0.01; P < 0.01) and 60-min (0.67 +/- 0.02 vs. 0.80 +/- 0.01; P < 0.01) defect count ratios (LAD/left circumflex coronary artery [LCx]) differentiated between the 2 groups, reflecting the greater diminution in coronary flow reserve in group 2 dogs (LAD/LCx flow ratios = 0.37 +/- 0.04 vs. 0.57 +/- 0.09; P < 0.01). Interestingly, coronary flow reserve in the reperfused zone of group 1 was diminished despite the absence of a stenosis. Thus, the difference in 99mTc-N-NOET uptake between the 2 groups was less than expected. CONCLUSION: In this canine myocardial infarction model with some coronary flow reserve preservation, 99mTc-N-NOET imaging can detect residual coronary stenoses. However, with more prolonged occlusion resulting in more severe endothelial or microvascular dysfunction, it may be difficult to distinguish varying degrees of vessel patency using any coronary flow reserve technique.

Tc-99m sestamibi defect magnitude predicts the amount of viable myocardium after coronary reperfusion despite the presence of severe residual stenosis.

BACKGROUND: Whether technetium-99m-labeled methoxyisobutyl isonitrile (Tc-99m sestamibi) imaging early after reperfusion can detect the amount of salvaged viable myocardium in the presence of a severe residual stenosis remains controversial. METHODS AND RESULTS: Nine dogs underwent total left anterior descending coronary artery (LAD) occlusion for 40 to 180 minutes followed by reperfusion through a flow-limiting stenosis. They were divided into 2 groups based on infarct size (group 1, <15% of risk area; group 2, > or =15%). Triphenyl tetrazolium chloride infarct size was measured by planimetry, and regional flow was quantified by radiolabeled microspheres. Mean infarct size was 9.3% +/- 3.0% of risk area in group 1 versus 51.1% +/- 4.8% in group 2 (P <.01). Tc-99m sestamibi was injected 30 minutes after reperfusion, when the LAD flows were comparable for group 1 (9 +/- 2 mL. min(-1)) and group 2 (9 +/- 1 mL. min(-1)). Left circumflex coronary artery flows were 33 +/- 5 and 32 +/- 9 mL. min(-1) for groups 1 and 2, respectively. Despite administration of Tc-99m sestamibi during diminished residual LAD flow after reperfusion, defect magnitude on ex vivo images in group 1 was significantly less severe than that in group 2, which had larger infarcts (0.71 +/- 0.02 vs 0.42 +/- 0.05, P <.01). This reflects greater salvage and more viability in group 1. CONCLUSION: Resting perfusion imaging with Tc-99m sestamibi accurately determined viability of the infarct zone despite reperfusion through a residual stenosis. Tc-99m sestamibi imaging may prove useful in the clinical setting for the prediction of the amount of salvaged myocardium.

Response to incremental doses of dobutamine early after reperfusion is predictive of the degree of myocardial salvage in dogs with experimental acute myocardial infarction.

OBJECTIVES: We sought to determine whether the inotropic response to dobutamine might be useful for estimating the extent of viable myocardium soon after reperfusion. BACKGROUND: Early identification of viable myocardium in the presence of severe left ventricular dysfunction after reperfusion is important for clinical decision making. METHODS: Nine open-chest dogs had left anterior descending coronary artery occlusion for 40 to 180 min, followed by gradual reperfusion. The systolic thickening response to incremental dobutamine doses was measured with ultrasonic crystals and regional flow by microspheres. RESULTS: Dogs were divided into two groups based on triphenyl tetralozium chloride infarct size (group 1: 9.3 +/- 3.0% risk area; group 2: 51.1 +/- 4.8%). In group 2 dogs with larger infarcts, regional flow during peak dobutamine was lower than it was in group 1 in endocardial (1.15 +/- 0.22 vs. 2.64 +/- 0.33 mL x min(-1) x g(-1)) and midwall (1.47 +/- 0.32 vs. 2.92 +/- 0.36 mL x min(-1) x g(-1)) layers, and endocardial flow in group 2 failed to increase from baseline (0.96 +/- 0.07 vs. 1.15 +/- 0.22 mL x min(-1) x g(-1)). Group 1 dogs demonstrated a dose dependent increase in systolic thickening with dobutamine versus a blunted response in group 2. The inotropic response to only 10 microg x kg(-1) x min(-1) of dobutamine was predictive of the degree of myocardial salvage. CONCLUSIONS: In the early postischemic stunning phase of reperfusion, the inotropic response to dobutamine is predictive of the degree of myocardial salvage and ultimate infarct size. The ability to distinguish between stunned versus necrotic myocardium early after reperfusion was most likely due to the presence of subendocardial flow reserve during dobutamine in dogs with predominantly salvaged myocardium.

Optimal timing for initial and redistribution technetium 99m-N-NOET image acquisition.

BACKGROUND: Bis (N-ethoxy, N-ethyl dithiocarbamato) nitrido technetium-99m (V) (Tc-99m-N-NOET) is a new Tc-99m-labeled myocardial perfusion imaging agent that redistributes. We sought to determine the optimal timing for acquiring initial and delayed images to maximize sensitivity for the detection of coronary stenoses. METHODS: Twelve anesthetized dogs with critical stenoses of the left anterior descending coronary artery were infused with adenosine (250 microg/kg/min) or MRE-0470, an adenosine A2a agonist (0.6 microg/kg/min x 10 minutes), and Tc-99m-N-NOET (8 mCi; 296 MBq) was injected intravenously at peak flow. Myocardial and lung Tc-99m-N-NOET activities were determined by serial quantitative imaging and arterial blood sampling was performed over 2 hours. RESULTS: Left anterior descending/left circumflex artery defect count ratios showed rapid redistribution during the first 10 minutes after Tc-99m-N-NOET injection (0.66 +/- 0.02 at 2 minutes to 0.73 +/- 0.01 at 10 minutes; P < .01). Redistribution was nearly complete by 120 minutes (defect ratio = 0.87 +/- 0.03; P < or = .01 vs 2 minutes). Lung activity fell significantly during the first 10 minutes from a heart/lung activity ratio of 1.07 +/- 0.05 (2 minutes) to 1.44 +/- 0.09 (10 minutes; P < or = .01). CONCLUSION: Initial stress Tc-99m-N-NOET images should be acquired within 10 minutes after injection, whereas delayed images can be obtained as early as 2 hours later. Lung activity clears rapidly, permitting acquisition of good-quality poststress cardiac images. These Tc-99m-N-NOET uptake and redistribution kinetics after vasodilator stress provide important information for designing clinical imaging protocols for optimal identification of inducible ischemia.

99mTc-N-NOET myocardial uptake reflects myocardial blood flow and not viability in dogs with reperfused acute myocardial infarction.

BACKGROUND: N-Ethoxy-N-ethyl-dithiocarbamato-nitrido-(99m)Tc ((99m)Tc-N-NOET) is a new neutral lipophilic (99m)Tc-labeled myocardial perfusion agent with a high first-pass extraction fraction and delayed redistribution kinetics after transient ischemia comparable to what is observed with (201)Tl. It is unknown whether the uptake of this tracer reflects myocardial viability or just reperfusion flow in the setting of a reperfused myocardial infarction. METHODS AND RESULTS: In 13 anesthetized open-chest dogs, the left anterior descending coronary artery was occluded for 180 minutes, followed by 180 minutes of reperfusion. (201)Tl and (99m)Tc-N-NOET were injected after either 60 (group 1, n=9) or 175 (group 2, n=4) minutes of reperfusion. Myocardial blood flow was measured by radioactive microspheres, and (201)Tl and (99m)Tc-N-NOET tissue activities were determined by gamma-well counting. Normalized myocardial blood flow in the central infarct zone fell from 0.80+/-0. 03 (SEM) and 0.89+/-0.01 at baseline to 0.18+/-0.04 and 0.13+/-0.02 during the occlusion in groups 1 and 2, respectively. Normalized (201)Tl activity in these segments was 0.39+/-0.04 and 0.43+/-0.04 and reflected myocardial viability rather than reperfusion flow (P<0. 001). Normalized (99m)Tc-N-NOET activity in the same segments was 0. 84+/-0.08 and 0.64+/-0.03, respectively (P<0.01 versus (201)Tl; P=NS versus reperfusion flow) and more accurately reflected reperfusion flow (0.99+/-0.17 and 0.70+/-0.04) than residual viability. CONCLUSIONS: The myocardial uptake of (99m)Tc-N-NOET reflects reperfusion myocardial blood flow and not viability in a canine model of reperfused acute myocardial infarction. The clinical use of early (99m)Tc-N-NOET imaging to assess the success of coronary reperfusion in patients with acute myocardial infarction should be investigated.

Myocardial uptake of (99m)Tc-N-NOET and (201)Tl during dobutamine infusion. Comparison with adenosine stress.

BACKGROUND: The myocardial uptake of (99m)Tc-sestamibi is attenuated by dobutamine stress, resulting in underestimation of ischemia. N-Ethyl-N-ethoxy-dithiocarbamato-N-(99m)Tc ((99m)Tc-N-NOET) is a new (99m)Tc-labeled perfusion agent that is highly extracted by the myocardium by a mechanism different from that defined for (99m)Tc-sestamibi. We therefore hypothesized that (99m)Tc-N-NOET uptake would not be attenuated by dobutamine and that (99m)Tc-N-NOET uptake would be comparable to (201)Tl uptake during dobutamine stress. METHODS AND RESULTS: In 28 open-chest dogs, after placement of a stenosis in the left anterior descending coronary artery that reduced flow reserve by >50%, adenosine (300 microgram. kg(-1). min(-1); n=15) or dobutamine (2.5 to 30 microgram. kg(-1). min(-1); n=13) was infused. During adenosine stress, the stenotic-to-normal activity ratio for (99m)Tc-N-NOET was 0.55+/-0.05. The stenotic-to-normal flow ratio was 0.33+/-0.04 at the time of (99m)Tc-N-NOET injection. During dobutamine stress, the stenotic-to-normal (99m)Tc-N-NOET activity ratio was 0.63+/-0.04, comparable to the (201)Tl activity ratio of 0.59+/-0.04. The stenotic-to-normal flow ratio was 0.47+/-0.04 at the time of (99m)Tc-N-NOET and (201)Tl injection. The relationship between (99m)Tc-N-NOET uptake and blood flow was comparable for adenosine and dobutamine stress, with no evidence of attenuation of (99m)Tc-N-NOET extraction by dobutamine. Conclusions-In the presence of coronary stenoses that reduced regional flow reserve, the myocardial uptake of (99m)Tc-N-NOET and (201)Tl are closely proportional to blood flow during both adenosine and dobutamine stress, suggesting that the adverse effect of dobutamine on (99m)Tc-sestamibi uptake is a tracer-specific phenomenon rather than a generalized effect. The clinical implication of this finding is that (99m)Tc-N-NOET might be preferable to (99m)Tc-sestamibi when used with dobutamine stress for detection of coronary stenoses.

Assessment of myocardial viability using 123I-labeled iodophenylpentadecanoic acid at sustained low flow or after acute infarction and reperfusion.

UNLABELLED: 123I-labeled iodophenylpentadecanoic acid (IPPA) is a synthetic fatty acid that may be useful for determination of myocardial viability. We investigated the uptake and clearance kinetics of this tracer in canine models of ischemia and infarction. METHODS: In protocol 1, 185 MBq (5 mCi) 123I-IPPA were injected intravenously in 19 dogs with 50% left anterior descending artery (LAD) flow reduction. In 9 dogs, 201TI was coinjected. In protocol 2, 5 dogs underwent LAD occlusion for 3 h, and 123I-IPPA was injected 60 min after reperfusion. All dogs had flow measured by microspheres, regional systolic thickening by ultrasonic crystals and measurements of postmortem risk area and infarct size. Tracer activities were quantified by gamma well counting and by serial imaging. RESULTS: In protocol 1 dogs with sustained low flow (50% +/- 4%) and absence of systolic thickening (-3.2% +/- 1%), 123I-IPPA defect magnitude (LAD/left circumflex artery [LCX] count ratios) decreased from 0.65 +/- 0.02 to 0.74 +/- 0.02 at 30 min and to 0.84 +/- 0.03 at 2 h (P < 0.01), indicative of rest redistribution. Final transmural 123I-IPPA LAD/LCX activity ratio (0.99 +/- 0.05) was significantly greater than the flow ratio (0.53 +/- 0.04) at injection, confirming complete rest redistribution. The final 123I-IPPA activity ratio was significantly greater than the 201TI ratio over the 2-h period (P < 0.01). In protocol 2 dogs that underwent 3 h of total LAD occlusion and reflow (infarct size = 51% +/- 13% of risk area), viability was overestimated with 123I-IPPA, because uptake averaged 64% of normal in the central necrotic region, where flow averaged < 10% of normal. CONCLUSION: These findings suggest that serial 123I-IPPA imaging may be useful for assessing myocardial viability under conditions of sustained low flow and myocardial asynergy, such as appears to exist in patients with chronic coronary artery disease and depressed left ventricular function. In contrast, 123I-IPPA given early after reperfusion following prolonged coronary occlusion overestimates the degree of viability and therefore may not provide useful information pertaining to the degree of myocardial salvage after reflow in the setting of acute myocardial infarction.

99mTc-tetrofosmin assessment of myocardial perfusion and viability in canine models of coronary occlusion and reperfusion.

UNLABELLED: The goal of this study was to determine whether 99mTc-tetrofosmin can assess regional flow heterogeneity when injected during sustained coronary artery occlusion and to estimate the degree of myocardial salvage and viability during coronary reperfusion. METHODS: In protocol 1, 99mTc-tetrofosmin, 201 TI and microspheres were injected during total left anterior descending (LAD) coronary artery occlusion in five anesthetized open-chested dogs. Protocol 2 dogs underwent LAD occlusion for either 60 min (n = 7) or 180 min (n = 6) followed by 105 min of reperfusion. 99mTc-tetrofosmin (10 mCi), 201TI (1 mCi) and microspheres were injected 90 min after reflow. In both protocols, myocardial 99mTc-tetrofosmin and 201TI activities were quantified from regions of interest on ex vivo images and by in vitro well counting. RESULTS: In protocol 1, there was a linear relationship between 201TI (r = 0.96) and 99mTc-tetrofosmin (r 0.92) activities and microsphere flow during the occlusion. In protocol 2, the LAD/left circumflex (LCx) defect count ratios for 99mTc-tetrofosmin and 201TI from images of myocardial slices were comparable in dogs undergoing either 1 or 3 h of LAD occlusion and 105 min of reperfusion. Similarly, the LAD/LCx in vitro count ratios were comparable between 201TI and 99mTc-tetrofosmin in 1 and 3 h occluded dogs, and significantly lower than the reperfusion flow when these tracers were injected. Uptake of both tracers was depressed to a greater extent in areas of severe ischemic damage. CONCLUSION: These data suggest that administration of 99mTc-tetrofosmin during coronary occlusion accurately delineates the flow heterogeneity. When given after reperfusion, 99mTc-tetrofosmin uptake was significantly reduced in reperfused, infarcted areas and was reflective of viability and the degree of myocardial salvage in addition to reperfusion flow. These experimental studies validate the clinical use of 99mTc-tetrofosmin for assessing persistent coronary artery occlusion, and infarct size and myocardial viability after reperfusion.

Myocardial uptake and redistribution of 99mTc-N-NOET in dogs with either sustained coronary low flow or transient coronary occlusion: comparison with 201Tl and myocardial blood flow.

BACKGROUND: 99mTc-N-NOET (NOET) is a new myocardial perfusion imaging agent that redistributes over time. We sought to better define the redistribution kinetics of NOET using open-chest canine models of sustained low coronary flow (protocol 1) and transient coronary occlusion followed by reflow (protocol 2). METHODS AND RESULTS: In protocol 1 (n=10), NOET and 201Tl were injected during low flow in the left anterior descending coronary artery (LAD) that was sustained for 2 hours. Protocol 2 dogs (n=6) were injected with NOET during 20 minutes of LAD occlusion followed by 2 hours of reflow. In both protocols, serial NOET planar images were acquired, and myocardial flow and 2-hour tracer activities were determined by gamma-well counting. Defect resolution was observed on images in both protocols. Initial defect count ratios, reflecting flow disparity at injection (0.66+/-0.03 and 0.57+/-0.04, respectively), increased over 2 hours (0.73+/-0.02 and 0.75+/-0.04, respectively; P<.001 versus initial). Quantitative imaging showed that NOET redistribution resulted from greater clearance from normal areas versus low-flow or transiently occluded areas. In protocol 1, 2-hour NOET and 201Tl stenotic-to-normal tissue activity ratios were similar (0.76+/-0.06 versus 0.73+/-0.04, P=NS) and higher than injection flow ratios (0.52+/-0.06 and 0.56+/-0.07, respectively, P<.001), consistent with tracer redistribution. In protocol 2, NOET redistributed to an even greater extent (injection flow ratio, 0.27+/-0.04; 2-hour tissue activity ratio, 0.84+/-0.03, P<.001). CONCLUSIONS: NOET is the first 99mTc-labeled myocardial imaging agent with kinetics similar to 201Tl in experimental models, permitting redistribution imaging. NOET appears to be a promising agent for assessing patients with coronary artery disease.

Myocardial 99mTc-tetrofosmin uptake during adenosine-induced vasodilatation with either a critical or mild coronary stenosis: comparison with 201Tl and regional myocardial blood flow.

BACKGROUND: Clinical studies have shown a comparable coronary stenosis detection rate between 99mTc-tetrofosmin and 201Tl but with smaller defect magnitudes for 99mTc-tetrofosmin. The goals of this study were to measure the first-pass extraction fraction (EF) of 99mTc-tetrofosmin in canine myocardium and to compare 99mTc-tetrofosmin with 201Tl uptake during adenosine-induced vasodilatation in dogs with various degrees of coronary stenosis. METHODS AND RESULTS: EF was calculated in 4 anesthetized, open-chest dogs after intracoronary administration of 125I-labeled albumin and 99mTc-tetrofosmin. In another 16 dogs with either critical (n=6) or mild (n= 10) left anterior descending coronary artery (LAD) stenoses, 201Tl and 99mTc-tetrofosmin were administered during adenosine infusion (250 microg x kg(-1) x min(-1)). Dogs were killed 5 minutes later, and tracer activities were determined by ex vivo imaging of heart slices and by well counting. Mean 99mTc-tetrofosmin EF was 54.0+/-3.7%. In the 6 critical-stenosis dogs, the LAD-to-left circumflex artery (LCx) microsphere flow ratio was 0.22+/-0.02 with adenosine. The LAD-to-LCx activity ratios were 0.37+/-0.04 for 201Tl and 0.67+/-0.05 for 99mTc-tetrofosmin (P<.01). For the 10 mild-stenosis dogs, the LAD-to-LCx flow ratio was 0.44+/-0.05. The 201Tl activity ratio was 0.58+/-0.04, compared with 0.81+/-0.04 for 99mTc-tetrofosmin (P<.01). Thus, in both groups, 99mTc-tetrofosmin uptake underestimated the flow disparity more than 201Tl. Similarly, magnitudes of ex vivo image defects were significantly greater for 201Tl than for 99mTc-tetrofosmin in both groups. CONCLUSIONS: In this canine model, relative underperfusion with adenosine stress is better resolved with 201Tl than with 99mTc-tetrofosmin and may be explained by the lower EF for 99mTc tetrofosmin. With clinical imaging, greater 201Tl attenuation and redistribution may lessen this advantage.

Effects of dobutamine stress on myocardial blood flow, 99mTc sestamibi uptake, and systolic wall thickening in the presence of coronary artery stenoses: implications for dobutamine stress testing.

BACKGROUND: Although dobutamine stress is used with both 99mTc sestamibi (sestamibi) myocardial perfusion imaging and echocardiography for detecting coronary artery stenoses, the impact of stenosis severity on test end points (myocardial sestamibi uptake and systolic thickening, respectively) has not been clearly defined. METHODS AND RESULTS: In 15 open-chest dogs, dobutamine (2.5 to 30 microg x kg(-1) x min(-1)) was infused after placement of an LAD stenosis that reduced (n=8) or abolished (n=7) flow reserve. In dogs with reduced flow reserve, the stenotic-to-normal sestamibi activity ratio (0.86+/-0.03) significantly underestimated the approximately 2-to-1 dobutamine-induced flow disparity at the time of sestamibi injection (flow ratio, 0.53+/-0.04; P<.001). Stenotic-zone thickening increased at low but not at higher doses of dobutamine (2.9+/-0.4 versus 4.2+/-0.4 mm in normal zone at peak dobutamine; P=.055) but did not fall below baseline (2.7+/-0.3 mm). Similarly, in dogs with absent flow reserve, the sestamibi activity ratio (0.78+/-0.02) underestimated the approximately 2.5-to-1 dobutamine-induced flow disparity (flow ratio, 0.41+/-0.05; P<.001), and failure to increase systolic thickening was observed in the stenotic zone (2.7+/-0.4 versus 4.6+/-0.3 mm in the normal zone at peak stress, P<.01). In both groups of dogs, myocardial sestamibi uptake and image defect magnitudes were less than expected for the dobutamine-induced hyperemia, suggesting that dobutamine adversely affects myocardial sestamibi binding. Finally, a significant reduction in stenotic-zone thickening was seen during postdobutamine recovery, consistent with myocardial stunning. CONCLUSIONS: In the presence of stenoses that reduced or abolished regional flow reserve, (1) myocardial sestamibi uptake significantly underestimated the dobutamine-induced flow heterogeneity, (2) a "failure to increase systolic thickening" rather than a reduction in thickening was observed during dobutamine stress, and (3) myocardial stunning was observed during postdobutamine recovery.

Kinetics of technetium-99m-teboroxime in reperfused nonviable myocardium.

UNLABELLED: This study evaluates 99mTc-teboroxime uptake and clearance kinetics in reperfused infarcted myocardium. METHODS: In 47 isolated buffer perfused rat hearts, 17 had normal flow (Control), 13 had 30 min of no flow followed by reflow (Noflow30) and 11 had 60 min of no flow followed by reflow (Noflow60). A 1-hr uptake phase was begun by normally perfusing all 41 hearts with 99mTc-teboroxime-doped buffer. After uptake, a 1-hr clearance phase was begun by switching to a 99mTc-teboroxime-free buffer. Technetium-99m activity was monitored with a Nal probe. Triton X-100, a membrane detergent, was given after tracer loading to six additional hearts. RESULTS: Control and Noflow30 hearts showed near linear and rapid uptake, while Noflow60 hearts showed curvilinear and significantly less uptake than predicted. All three of these groups showed biexponential clearance. Early t1/2 was not significantly different for the three groups (Control = 6.3 +/- 1.9 sem min, Noflow30 = 5.4 +/- 1.3 min, Noflow60 = 8.9 +/- 2.8 min). Late t1/2 was significantly shorter for Noflow30 (52.3 +/- 5.3 min) and the Noflow60 (50.9 +/- 4.3 min), compared to the Control hearts (74.1 +/- 6.6 min, p < 0.05). One-hour fractional clearances were significantly greater for the Noflow30 and Noflow60 hearts (0.65 +/- 0.01 and 0.65 +/- 0.01, respectively) compared to the Controls (0.55 +/- 0.01, p < 0.05). In hearts given Triton X-100, there was a markedly increased fractional clearance of 0.96 +/- 0.01 (p < 0.01 compared to Controls). Electron microscopy showed evidence of mild injury in the Noflow30 hearts, more extensive damage in the Noflow60 hearts and severe irreversible injury in Triton X-100 hearts. CONCLUSION: Myocardial 99mTc-teboroxime uptake and clearance kinetics are significantly altered in mildly and moderately injured reperfused myocardium. Technetium-99m-teboroxime clearance is markedly accelerated in the setting of overt damage to cell and organelle membranes induced by Triton X-100.

Pharmacological stress thallium scintigraphy with 2-cyclohexylmethylidenehydrazinoadenosine (WRC-0470). A novel, short-acting adenosine A2A receptor agonist.

BACKGROUND: Pharmacological stress imaging with adenosine or dipyridamole is associated with a high incidence of side effects, including hypotension, chest pain, AV conduction abnormalities, and bronchospasm. Although the desired coronary vasodilatory response is mediated primarily by the adenosine A2A receptors, these side effects result from stimulation of the A1, A2B, or A3 adenosine receptors. We hypothesized that a selective adenosine A2A receptor agonist would induce coronary vasodilatation appropriate for pharmacological stress imaging, without evoking adenosine receptor-mediated side effects. METHODS AND RESULTS: Infusions of a potent and selective A2A adenosine receptor agonist, WRC-0470 (0.1 to 3 micrograms kg-1. min-1 for 10 minutes), to five open-chest dogs produced dose-related left anterior descending (LAD) and left circumflex (LCx) coronary artery vasodilatation without altering mean arterial pressure, heart rate, left atrial pressure, or left ventricular dP/dt. In the same dogs, adenosine (300 micrograms . kg-1. min-1 for 4 minutes) produced coronary vasodilatation that was limited by significant hypotension. To determine the utility of WRC-0470 for pharmacological stress imaging, the hemodynamic responses to WRC-0470 (0.6 microgram.kg-1.min-1 for 10 minutes) and adenosine (250 micrograms.kg-1.min-1 for 4 minutes) were compared in dogs with critical LAD stenoses. 201T1 was injected at the peak WRC-0470 stress response. WRC-0470 increased LCx flow nearly fivefold but did not significantly lower mean arterial pressure. Anteroseptal defects were readily apparent in slice images from all dogs. The mean defect ratio (LAD/LCx) was 0.59 +/- 0.06. CONCLUSIONS: The potent A2A-selective adenosine receptor agonist WRC-0470 is a short-acting coronary vasodilator with potential utility for pharmacological stress perfusion imaging.

Comparison between thallium-201 and technetium-99m-tetrofosmin uptake with sustained low flow and profound systolic dysfunction.

UNLABELLED: Technetium-99m-tetrofosmin uptake was compared to that of 201Tl in the setting of low flow and systolic dysfunction. METHODS: In nine open-chested dogs, a severe left anterior descending (LAD) coronary artery stenosis resulted in a 54.3% mean flow reduction and decreased left ventricular thickening from 21% +/- 1% to -3 +/- 2%. After 30 min, 37 MBq (1 mCi) of 201Tl and microspheres were injected and initial and 2-hr redistribution images acquired. Two hours later, 370 MBq (10 mCi) of 99mTc-tetrofosmin and microspheres were injected and an image was obtained. LAD: left circumflex (LCX) count ratios for both tracers and flows were calculated by well counting postmortem, and 201Tl and 99mTc-tetrofosmin defect magnitudes were determined by quantitative image analysis. RESULTS: LAD:LCx flow ratios were similar during 201Tl and 99mTc-tetrofosmin injections (0.48 +/- 0.04 versus 0.49 +/- 0.05, p = n.s.). Final 201Tl activity (0.66 +/- 0.04) was significantly higher than 99mTc-tetrofosmin (0.55 +/- 0.05; p < 0.05). LAD/LCx 99mTc-tetrofosmin image defect count ratio was similar to 201Tl defect count ratio on the initial rest 201Tl scan (0.57 +/- 0.03 versus 0.56 +/- 0.02, p = ns), but significantly less than 201Tl defect count ratio at 2 hr (0.57 +/- 0.03 versus 0.65 +/- 0.02, p < 0.05). CONCLUSION: In a low-flow model with profound systolic dysfunction, myocardial 99mTc-tetrofosmin uptake ( > 50%) reflective of viability was observed in the asynergic zone perfused by the stenotic LAD.

Comparison of thallium-201 resting redistribution with technetium-99m-sestamibi uptake and functional response to dobutamine for assessment of myocardial viability.

BACKGROUND: 201Tl scintigraphy is useful for determination of viability in patients with coronary artery disease and depressed left ventricular function. Whether 99mTc sestamibi is adequate for viability detection remains controversial. The primary goal of this study was to compare 99mTc-sestamibi uptake with 201Tl uptake in canine models of sustained low flow and regional asynergy for determination of viability. A secondary objective was to compare myocardial uptake of these tracers with the functional response to low-dose dobutamine. METHODS AND RESULTS: In protocol 1, 14 open-chested, anesthetized dogs with a 50% reduction in resting left anterior descending coronary artery (LAD) flow underwent 1 hour of transient LAD occlusion followed by reperfusion through the severe stenosis. Then 1.0 mCi of 201Tl was injected, and serial imaging was performed 5 minutes and 2 hours later. After acquisition of the delayed 201Tl image, 10 mCi of 99mTc sestamibi was injected, and imaging was repeated 45 minutes later. No significant difference was seen between the 201Tl defect ratio (LAD/left circumflex coronary artery [LCx]) on redistribution images (0.62 +/- 0.02) and 99mTc-sestamibi defect ratio (0.60 +/- 0.02). Similarly, LAD/LCx activity ratios by gamma-well counting were comparable (0.62 +/- 0.02 versus 0.59 +/- 0.04) and reflected the flow decrement. Systolic thickening was -11 +/- 3% at the time of tracer injection. In protocol 2, 16 dogs underwent serial 201Tl and 99mTc-sestamibi imaging during a 50% reduction in LAD flow with no superimposed transient LAD occlusion. In this model, the 99mTc-sestamibi LAD/LCx image defect ratio (0.61 +/- 0.03) was significantly less than the 201Tl redistribution image defect ratio (0.66 +/- 0.03, P < .01). In 10 dogs, the stenosis was released, resulting in a significant increase in systolic thickening (P = .003), which increased further in response to 5 micrograms.kg-1.min-1 of dobutamine (P = .02). In contrast, thickening increased only from -7 +/- 3% to 2 +/- 4% (P = .004) in response to dobutamine infusion in the remaining 6 dogs with persistent severe LAD stenoses. In protocol 3, 5 dogs received both 201Tl and 99mTc sestamibi to compare the degree of delayed redistribution between tracers at 2 hours. The LAD/LCx microsphere flow ratios when 201Tl and 99mTc sestamibi were injected were 0.44 +/- 0.06 and 0.43 +/- 0.05 (P = NS), respectively. The LAD/LCx activity ratio by gamma-well counting was greater for 201Tl (0.56 +/- 0.08) than 99mTc sestamibi (0.50 +/- 0.07) at 2 hours of redistribution (P < .05), indicating greater redistribution for 201Tl. The LAD/LCx 99mTc-sestamibi defect ratios on serial imaging improved from 0.49 +/- 0.07 to 0.52 +/- 0.07 (P = .0005), consistent with a slight amount of 99mTc-sestamibi redistribution. In protocol 4, no difference between 201Tl and 99mTc-sestamibi defect magnitudes was seen in 4 dogs undergoing 3 hours of total LAD occlusion and ligation of visible coronary collaterals. Infarct size was 68 +/- 19% of the risk area. CONCLUSIONS: Although 99mTc-sestamibi and 201Tl defect magnitudes and regional activities were comparable in dogs with sustained low coronary flows and superimposed subendocardial infarctions and in dogs with large infarctions, approximately 5% more 201Tl than 99mTc-sestamibi uptake was observed in dogs with chronic low flow and severe systolic dysfunction. Substantial 99mTc-sestamibi uptake in asynergic zones was observed in this low-flow model, with some slight resting 99mTc-sestamibi redistribution observed on serial images. Systolic thickening was negligibly enhanced during dobutamine infusion in dogs with sustained low flow, whereas 201Tl uptake was only mildly reduced.

Technetium-99m sestamibi kinetics in reperfused canine myocardium.

The purpose of the current study was to clarify the myocardial kinetics of technetium-99m sestamibi when the latter is administered during reperfusion. Sestamibi has in the past been given to patients following thrombolytic therapy to document reperfusion and assess salvage. However, the factors which affect sestamibi kinetics during reperfusion are not clearly defined. In this study the left circumflex coronary artery was occluded for 2 h in six dogs (group 1) and for 3 h in six dogs (group 2), followed by reperfusion. Five additional dogs were not reperfused (group 3). Sestamibi was administered during reperfusion in groups 1 and 2, and during ongoing occlusion in group 3. Regional myocardial sestamibi activity was monitored for 3 h using miniature implanted radiation detectors and gamma camera imaging. Group 1 dogs had no infarcts, group 2 had moderate infarcts (mean: 13.9%), and group 3 had large infarcts (mean: 25.2%). Three-hour fractional myocardial clearances were significantly greater for reperfused infarcted (group 2) (0.23 +/- 0.02 SEM) and for nonreperfused infarcted myocardium (group 3) (0.24 +/- 0.02) compared to control (0.10 +/- 0.01) and reperfused noninfarcted myocardium (group 1) (0.07 +/- 0.02; P < 0.01). Quantitative image analysis demonstrated a significant reduction in the left circumflex/left anterior descending count ratios from initial to final scans for group 2 (0.74 +/- 0.03 to 0.65 +/- 0.03, P < 0.05), and a trend towards a reduction in the count ratios from initial to final scans for group 3 (0.38 +/- 0.04 to 0.30 +/- 0.04; P = 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial technetium-99m-teboroxime uptake during adenosine-induced hyperemia in dogs with either a critical or mild coronary stenosis: comparison to thallium-201 and regional blood flow.

UNLABELLED: Experimental studies have shown 99mTc-teboroxime to have a higher first-pass myocardial extraction, exceeding that of 201Tl with nearly linear initial myocardial uptake over a wide range of coronary flows. The goal of this study was to quantitatively compare teboroxime with 201Tl for the assessment of a regional coronary flow imbalance when administered during adenosine vasodilation in dogs with either critical or mild LAD stenoses. METHODS: Twenty-four anesthetized dogs with either critical (n = 10) or mild (n = 14) LAD stenoses were given an i.v. infusion of adenosine (300 micrograms/kg/min). When LCx flow was maximal, 201Tl, teboroxime and microspheres were simultaneously injected and the dogs were killed either 2 or 4 min later. Regional 201Tl, teboroxime activities and myocardial blood flow were determined by gamma well counting and ex vivo imaging of 99mTc-teboroxime activity in myocardial heart slices was performed. RESULTS: In both the critical and mild stenosis groups, the LAD/LCx zone ratios in dogs killed 2 min after tracer injection for both 201Tl (0.31 +/- 0.07, 0.63 +/- 0.05) and teboroxime (0.38 +/- 0.09, 0.72 +/- 0.04) significantly underestimated the microsphere flow ratio (0.18 +/- 0.05, 0.43 +/- 0.05) (p < or = 0.01), but the degree of underestimation was greater for teboroxime compared with Tl (p < or = 0.05). CONCLUSION: In dogs with either critical or mild LAD stenoses, as early as 2 min after tracer injection, the 201Tl activity ratio more accurately assessed the adenosine-induced regional flow heterogeneity than did teboroxime. These results highlight the importance of an ultra-fast imaging protocol when using teboroxime with pharmacologic stress.

Comparison between 201Tl and 99mTc sestamibi uptake during adenosine-induced vasodilation as a function of coronary stenosis severity.

BACKGROUND: Myocardial uptake of either 201Tl or 99mTc-sestamibi (sestamibi) is known to plateau at high coronary flow rates. However, few direct comparisons have been made between these tracers to determine what effect differences in the uptake plateau for the two tracers may have on the detection of coronary stenoses of various severities. METHODS AND RESULTS: Twenty-two dogs were instrumented with flow transducers on the left anterior descending (LAD) and circumflex (LCx) arteries. In 6 nonstenotic dogs, adenosine was infused directly into the LAD, whereas 16 dogs with either critical (n = 7) or mild (n = 9) LAD stenoses received an intravenous infusion. At peak flow, 201Tl (0.5 mCi), sestamibi (5 to 8 mCi), and radiolabeled microspheres were injected simultaneously. Five minutes later, dogs were killed, and ex vivo imaging of heart slices and gamma-well counting of multiple myocardial samples was performed. Neither 201Tl nor sestamibi uptake increased in direct proportion to flow. In the 6 nonstenotic dogs, a fivefold increase in LAD flow increased 201Tl and sestamibi uptake by only 202 +/- 6% and 138 +/- 4%, respectively (P < .0001). In the dogs with critical stenosis, the ratios of stenotic to normal activity by well counting for 201Tl (0.37 +/- 0.05) and sestamibi (0.53 +/- 0.06) underestimated the microsphere-determined flow disparity (0.17 +/- 0.03) (P < .005), but the degree of underestimation was greater for sestamibi (P = .001). Similarly, in the dogs with mild stenosis, the stenotic-to-normal ratio for 201Tl (0.62 +/- 0.04) approximated the flow ratio (0.43 +/- 0.04) better than sestamibi (0.79 +/- 0.03) (P < .0001). Sestamibi defects, however, were visually identifiable on the images of the myocardial slices. By image quantification, sestamibi defect magnitude (LAD-to-LCx count ratio) in the critical stenosis group (0.62 +/- 0.05) was significantly less than in the mild stenosis group (0.80 +/- 0.02) (P < .01). CONCLUSIONS: Thus, with adenosine-induced hyperemic flow, both 201Tl and sestamibi significantly underestimated the magnitude of the flow disparity between stenotic and normal perfusion beds. The degree of underestimation was greater for sestamibi. The clinical implication of these experimental findings for vasodilator perfusion imaging remains to be determined, since factors such as greater redistribution and scatter with 201Tl could offset its advantages.